Tumor Microenvironment: The Functions and Underlying Mechanisms of Cellular and Non-cellular Components During Cancer Progression and Metastasis

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Original Research
14 November 2023
Iron affects the sphere-forming ability of ovarian cancer cells in non-adherent culture conditions
Anna Martina Battaglia
9 more and 
Francesco Costanzo
3D tumor spheroids derived from HEY and PEO1 cells show a reduction of intracellular LIP. (A) Western blot of FtH1, CD71, and FPN in HEY and PEO1 cells (3D vs. 2D). γ-TUB was used as loading control. Flow cytometry analysis of LIP (B) and ROS (C) amounts quantified by using CA-AM and CM-H2DCFDA respectively, in HEY and PEO1 cells cultured in both 2D, and 3D condition. (D) PI flow cytometric analysis of HEY and PEO1 cells (3D vs. 2D); % of dead cells (PI positive) are reported in each plot. Representative images of their derived 3D tumor spheroids (Scale bar: 100 μm; Magnification: ×20) and relative histogram of the % of dead cells are reported on the right. qRT-PCR of stemness (E) and EMT (F) markers in HEY and PEO1 cells (3D vs. 2D). Results are presented as mean ± SD from three independent experiments. *p-value <0.05; **p-value <0.01; ns: not significant.

Introduction: Detachment from the extracellular matrix (ECM) is the first step of the metastatic cascade. It is a regulated process involving interaction between tumor cells and tumor microenvironment (TME). Iron is a key micronutrient within the TME. Here, we explored the role of iron in the ability of ovarian cancer cells to successfully detach from the ECM.

Methods: HEY and PEO1 ovarian cancer cells were grown in 3D conditions. To mimic an iron rich TME, culture media were supplemented with 100 μM Fe3+. Cell mortality was evaluated by cytofluorimetric assay. The invasive potential of tumor spheroids was performed in Matrigel and documented with images and time-lapses. Iron metabolism was assessed by analyzing the expression of CD71 and FtH1, and by quantifying the intracellular labile iron pool (LIP) through Calcein-AM cytofluorimetric assay. Ferroptosis was assessed by quantifying mitochondrial reactive oxygen species (ROS) and lipid peroxidation through MitoSOX and BODIPY-C11 cytofluorimetric assays, respectively. Ferroptosis markers GPX4 and VDAC2 were measured by Western blot. FtH1 knockdown was performed by using siRNA.

Results: To generate spheroids, HEY and PEO1 cells prevent LIP accumulation by upregulating FtH1. 3D HEY moderately increases FtH1, and LIP is only slightly reduced. 3D PEO1upregulate FtH1 and LIP results significantly diminished. HEY tumor spheroids prevent iron import downregulating CD71, while PEO1 cells strongly enhance it. Intracellular ROS drop down during the 2D to 3D transition in both cell lines, but more significantly in PEO1 cells. Upon iron supplementation, PEO1 cells continue to enhance CD71 and FtH1 without accumulating the LIP and ROS and do not undergo ferroptosis. HEY, instead, accumulate LIP, undergo ferroptosis and attenuate their sphere-forming ability and invasiveness. FtH1 knockdown significantly reduces the generation of PEO1 tumor spheroids, although without sensitizing them to ferroptosis.

Discussion: Iron metabolism reprogramming is a key event in the tumor spheroid generation of ovarian cancer cells. An iron-rich environment impairs the sphere-forming ability and causes cell death only in ferroptosis sensitive cells. A better understanding of ferroptosis sensitivity could be useful to develop effective treatments to kill ECM-detached ovarian cancer cells.

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12 citations
Review
16 May 2023
Lipid metabolism and tumor immunotherapy
Yue Wang
4 more and 
Huazhong Cai

In recent years, the relationship between lipid metabolism and tumour immunotherapy has been thoroughly investigated. An increasing number of studies have shown that abnormal gene expression and ectopic levels of metabolites related to fatty acid synthesis or fatty acid oxidation affect tumour metastasis, recurrence, and drug resistance. Tumour immunotherapy that aims to promote an antitumour immune response has greatly improved the outcomes for tumour patients. However, lipid metabolism reprogramming in tumour cells or tumour microenvironment-infiltrating immune cells can influence the antitumour response of immune cells and induce tumor cell immune evasion. The recent increase in the prevalence of obesity-related cancers has drawn attention to the fact that obesity increases fatty acid oxidation in cancer cells and suppresses the activation of immune cells, thereby weakening antitumour immunity. This article reviews the changes in lipid metabolism in cells in the tumour microenvironment and describes the relationship between lipid metabolism reprogramming in multiple cell types and tumour immunotherapy.

4,756 views
13 citations
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Frontiers in Cell and Developmental Biology

Cell Adhesion Molecules: Pivotal Regulators of Metabolism in Cancer Progression
Edited by Sandeep P Dumbali, Simon Calaminus, Nathan Ward, Claudia Tanja Mierke
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